Abstract
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Objectives Despite recent improvements in the survival rates for cervical cancer, novel treatment strategies are required to improve distant metastasis-free survival. The sodium iodine symporter (NIS) gene has been applied for in vivo imaging and cancer therapy. In this study, we examined the therapeutic effects of NIS gene under the control of tumor-specific human telomerase reverse transcriptase (hTERT) promoter using 188Re in vivo.
Methods We constructed two lentiviral vectors under the control of hTERT promoter respectively expressing NIS or enhanced green fluorescent protein (EGFP). We stably transfected the vector expressing EGFP into various tumor cells and normal cells to identify the tumor-specific character of hTERT promoter. Then the vector expressing NIS was stably transfected into Hela cells to create Hela-TERTNIS cells. Hela and Hela-TERTNIS tumor xenografts were established in nude mice. The 188Re distribution in vivo were measured using micro-SPECT/CT imaging. The therapeutic effects of 188Re were assessed over 21 days by measuring tumor volume and immunohistochemical staining of the excised tumors.
Results Tumor cells showed a much higher lever of EGFP expression under hTERT promoter than normal cells. qPCR and Western blotting confirmed that Hela-TERTNIS cells expressed high levels of NIS mRNA and protein. Hela-TERTNIS cells and xenografts significantly took up and accumulated more 188Re than Hela cells and xenografts. In vitro and in vivo, 188Re significantly reduced the clonogenic survival of Hela-TERTNIS cells and inhibited the growth of Hela-TERTNIS xenografts. At the end of 188Re therapy, Hela-TERTNIS xenograft tumors expressed higher levels of NIS and caspase-3 and lower levels of Ki-67.
Conclusions NIS gene-mediated 188Re uptake into Hela cells showed a significant therapeutic effect in an in vivo model of cervical cancer. The use of hTERT protomer provided a tumor-specific targeting uptake of 188Re and reduced damage to normal tissues.